1. Field of the Invention
The present invention is concerned with substituted piperazine compounds, therapeutic dosage forms including one or more of the compounds, and methods for treating diseases in mammals, and in particular, in a human in a therapy selected from the group including protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal""s (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
2. Description of the Art
U.S. Pat. No. 4,567,264, the specification of which is incorporated herein by reference, discloses a class of substituted piperazine compounds that includes a compound known as ranolazine, (xc2x1)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide, and its pharmaceutically acceptable salts, and their use in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise-induced angina, and myocardial infarction.
U.S. Pat. No. 5,506,229, which is incorporated herein by reference, discloses the use of ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissues experiencing a physical or chemical insult, including cardioplegia, hypoxic or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants. In particular, ranolazine is particularly useful for treating arrhythmias, variant and exercise-induced angina, and myocardial infarction by partially inhibiting cardiac fatty acid oxidation. Conventional oral and parenteral ranolazine formulations are disclosed, including controlled release formulations. In particular, Example 7D of U.S. Pat. No. 5,506,229 describes a controlled release formulation in capsule form comprising microspheres of ranolazine and microcrystalline cellulose coated with release controlling polymers.
Despite the important discovery that ranolazine is a very useful cardiac therapeutic agent, there remains a need for compounds that are partial fatty acid oxidation inhibitors that have a half-life greater than ranolazine and that have activities as least similar to ranolazine.
This invention includes novel substituted piperazine compounds that are partial fatty acid oxidation inhibitors with good therapeutic half-lives.
This invention also includes novel substituted piperazine compounds that can be administered to a mammal to protect skeletal muscles against damage resulting from trauma, to protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal""s (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
This invention includes a class of substituted piperazine compounds having the 
following formula:
wherein m=1 or 2 or 3;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C1-5 alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22;
R6, R7 and R8 each independently selected from the group consisting of hydrogen or C1-5 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C1-4 alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, CO2R23, CON(R23)2 or aryl, wherein R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein R11 and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 4 carbon atoms and wherein R9 and R10 or R11 and R12 or R13 and R14 or R15 and R16 may join to form a spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms;
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22 or wherein R17 and R18 may join together to form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, or wherein R17 and R18 or R18 and R19 or R19 and R20 or R20 and R21 may combine to form a saturated ring including from 3 to 6 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom;
R22 is selected from the group consisting of C1-15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, Oxe2x80x94C1-6 alkyl, CF3, or heteroaryl; and
R23 is selected from the group consisting of H, C1-15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alky, CN, xe2x80x94Oxe2x80x94C1-6 alky, or CF3.
In another embodiment, this invention is a substituted piperazine compound selected from the group consisting of N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)propyl]piperazinyl}acetamide; 2-[4-(3-(2H-benzo[d]1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-phenylpropyl]piperazinyl}acetamide; N-(2,6-dimethylphenyl)-2-{4-[4-(4-methoxyphenyl)-2-hydroxybutyl]piperazinyl}acetamide, 2-{4-[4-(2,6-difluorophenyl)-2-hydroxybutyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl}acetamide, 2-(4-{4-[4-(tert-butyl)phenyl]-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[4-(2-fluorophenyl)-2-hydroxybutyl]piperazinyl}acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-4-[4-(trifluoromethyl)phenyl]butyl}piperazinyl)acetamide, 2-[4-(3-(2H-benzo[d]1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl]piperazinyl}-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl]acetamide, N-(2,6-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)-2-hydroxy-pentyl]piperazinyl}acetamide, and N-(2,6-dimethylphenyl)-2-{4-[5-(2-chlorophenyl)-2-hydroxy-pentyl]piperazinyl}acetamide.
In yet another embodiment, this invention is a method for administering one or more composition of this invention to a mammal in a treatment selected from the group consisting of protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal""s (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
This invention concerns substituted piperazine compounds having the following formula: 
wherein m=0, 1 or 2 or 3;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22;
R6, R7 and R8 each independently selected from the group consisting of hydrogen or C1-15 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C1-4 alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, CO2R23, CON(R23)2 or aryl, wherein R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein R11 and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 4 carbon atoms and wherein R9 and R10 or R11 and R12 or R13 and R14 or R15 and R16 may join to form a spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms;
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22 or wherein R17 and R18 may join together may join together to form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or wherein R17 and R18 or R18 and R19 or R19 and R20 or R20 and R21 may combine to form a saturated ring including from 3 to 6 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom and wherein the ring may be optionally substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23 N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R232, COR23, CO2R23, CON(R23)2, NR23SO2R23, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, or SO2R22;
R22 is selected from the group consisting of C1-15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, Oxe2x80x94C1-6 alkyl, CF3, or heteroaryl; and
R23 is selected from the group consisting of H, C1-15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl, CN, xe2x80x94Oxe2x80x94 C1-6 alkyl, or CF3.
In preferred compositions of this invention, m=0, 1 or 2 or 3; R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C1-4 alkyl; R6, R7 and R8 each independently selected from the group consisting of hydrogen and C1-3 alkyl; R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-4 alkyl, or R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl, or wherein R11 and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join together to form a ring including from 1 to 4 carbon atoms wherein R9, R10, R11, R12, R13, R14, R15 and R16 are not all hydrogen; and R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR22, S(O)R22, SO2R22, SON(R22)2, CON(R22)2, C1-4 alkyl or R17 and R18 may together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, and phenyl.
In other preferred compounds, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C1-2 alkyl wherein R22 is a C1-3 alkyl; R6, R7 and R8 are each independently selected from the group consisting of hydrogen and methyl; R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-2 alkyl, or R9 and R10 may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that R9, R10, R11, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen and wherein R11 and R13 or R19 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join to form a ring including from 1 to 4 carbon atoms and R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR22, and C1-4 alkyl wherein R22 is C1-3 alkyl, and wherein R17 and R18 may together form a substituent selected from the group consisting of xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 and phenyl.
In still other preferred compounds, m=1 or 2; R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C1-4 alkyl where R22 is a C1-3 alkyl; R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from hydrogen and methyl; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22, C1-3 alkyl where R22 is methyl, or R17 and R18 may together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, or R18 and R19 may together form xe2x80x94OCH2Oxe2x80x94.
In more preferred compounds, m=1 or 2;; R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from methyl and hydrogen; R9, R10, R11, R12, R13, R14, R15 and R16 are each hydrogen; and R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 wherein R22 is methyl, or R17 and R18 may together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, or R18 and R19 may together form xe2x80x94OCH2Oxe2x80x94.
In yet other preferred compounds, m=1 or 2;; R1 and R5 are methyl; R2, R3, R4 R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are hydrogen; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, OR22 wherein R22 is methyl, or R17 and R18 may together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, or R18 and R19 may together form xe2x80x94OCH2Oxe2x80x94.
In still other preferred compounds, R1 and R5 are methyl; R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are hydrogen; R17 is selected from the group consisting of hydrogen, chloro, fluoro and methoxy; R18 is selected from hydrogen and methoxy; R19 is selected from hydrogen and methoxy; R20 is hydrogen; R21 is selected from hydrogen and chloro, or R17 and R18 may together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, or R18 and R19 may together form xe2x80x94OCH2Oxe2x80x94.
Most preferably, the substituted piperazine compounds of this invention are selected from N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)propyl]piperazinyl}acetamide; 2-[4-(3-(2H-benzo[d]1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-phenylpropyl]piperazinyl}acetamide, N-(2,6-dimethylphenyl)-2-{4-[4-(4-methoxyphenyl)-2-hydroxybutyl]piperazinyl}acetamide, 2-{4-[4-(2,6-difluorophenyl)-2-hydroxybutyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl}acetamide, 2-(4-{4-[4-(tert-butyl)phenyl]-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[4-(2-fluorophenyl)-2-hydroxybutyl]piperazinyl}acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-4-[4-(trifluoromethyl)phenyl]butyl}piperazinyl)acetamide, 2-[4-(3-(2H-benzo[d]1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl]piperazinyl}-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl]acetamide, N-(2,6-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)-2-hydroxy-pentyl]piperazinyl}acetamide, and N-(2,6-dimethylphenyl)-2-{4-[5-(2-chlorophenyl)-2-hydroxy-pentyl]piperazinyl}acetamide.
The following definitions apply to terms as used herein.
xe2x80x9cHaloxe2x80x9d or xe2x80x9cHalogenxe2x80x9dxe2x80x94alone or in combination means all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), iodo (I).
xe2x80x9cHydroxylxe2x80x9d refers to the group xe2x80x94OH.
xe2x80x9cThiolxe2x80x9d or xe2x80x9cmercaptoxe2x80x9d refers to the group xe2x80x94SH.
xe2x80x9cAlkylxe2x80x9dxe2x80x94alone or in combination means an alkane-derived radical containing from 1 to 20, preferably 1 to 15, carbon atoms (unless specifically defined). It is a straight chain alkyl, branched alkyl or cycloalkyl. Preferably, straight or branched alkyl groups containing from 1-15, more preferably 1 to 8, even more preferably 1-6, yet more preferably 1-4 and most preferably 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. The term xe2x80x9clower alkylxe2x80x9d is used herein to describe the straight chain alkyl groups described immediately above. Preferably, cycloalkyl groups are monocyclic, bicyclic or tricyclic ring systems of 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like. Alkyl also includes a straight chain or branched alkyl group that contains or is interrupted by a cycloalkyl portion. The straight chain or branched alkyl group is attached at any available point to produce a stable compound. Examples of this include, but are not limited to, 4-(isopropyl)-cyclohexylethyl or 2-methyl-cyclopropylpentyl. A substituted alkyl is a straight chain alkyl, branched alkyl, or cycloalkyl group defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like.
xe2x80x9cAlkenylxe2x80x9dxe2x80x94alone or in combination means a straight, branched, or cyclic hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferably 2-8, most preferably 2 to 4 carbon atoms with at least one, preferably 1-3, more preferably 1-2, and most preferably one, carbon to carbon double bond. In the case of a cycloalkyl group, conjugation of more than one carbon to carbon double bond is not such as to confer aromaticity to the ring. Carbon to carbon double bonds may be either contained within a cycloalkyl portion, with the exception of cyclopropyl, or within a straight chain or branched portion. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, cyclohexenyl, cyclohexenylalkyl and the like. A substituted alkenyl is the straight chain alkenyl, branched alkenyl or cycloalkenyl group defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, or the like attached at any available point to produce a stable compound.
xe2x80x9cAlkynylxe2x80x9dxe2x80x94alone or in combination means a straight or branched hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferably 2-8, most preferably 2-4, carbon atoms containing at least one, preferably one, carbon to carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. A substituted alkynyl refers to the straight chain alkynyl or branched alkynyl defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like attached at any available point to produce a stable compound.
xe2x80x9cAlkyl alkenylxe2x80x9d refers to a group xe2x80x94Rxe2x80x94CRxe2x80x2xe2x95x90CRxe2x80x2xe2x80x3Rxe2x80x3xe2x80x3, where R is lower alkyl, or substituted lower alkyl, Rxe2x80x2, Rxe2x80x2xe2x80x3, Rxe2x80x3xe2x80x3 may independently be hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.
xe2x80x9cAlkyl alkynylxe2x80x9d refers to a groups xe2x80x94RCxe2x89xa1CRxe2x80x2 where R is lower alkyl or substituted lower alkyl, Rxe2x80x2 is hydrogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.
xe2x80x9cAlkoxyxe2x80x9d denotes the group xe2x80x94OR, where R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl as defined.
xe2x80x9cAlkylthioxe2x80x9d denotes the group xe2x80x94SR, xe2x80x94S(O)n=1xe2x88x922xe2x80x94R, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl as defined herein.
xe2x80x9cAcylxe2x80x9d denotes groups xe2x80x94C(O)R, where R is hydrogen, lower alkyl substituted lower alkyl, aryl, substituted aryl and the like as defined herein.
xe2x80x9cAryloxyxe2x80x9d denotes groups xe2x80x94OAr, where Ar is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group as defined herein.
xe2x80x9cAminoxe2x80x9d denotes the group NRRxe2x80x2, where R and Rxe2x80x2 may independently by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined herein or acyl.
xe2x80x9cAmidoxe2x80x9d denotes the group xe2x80x94C(O)NRRxe2x80x2, where R and Rxe2x80x2 may independently by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl as defined herein.
xe2x80x9cCarboxylxe2x80x9d denotes the group xe2x80x94C(O)OR, where R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, and substituted hetaryl as defined herein.
xe2x80x9cArylxe2x80x9dxe2x80x94alone or in combination means phenyl or naphthyl optionally carbocyclic fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members and/or optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like.
xe2x80x9cSubstituted arylxe2x80x9d refers to aryl optionally substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
xe2x80x9cHeterocyclexe2x80x9d refers to a saturated, unsaturated, or aromatic carbocyclic group having a single ring (e.g., morpholino, pyridyl or furyl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo[b]thienyl) and having at least one hetero atom, such as N, O or S, within the ring, which can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
xe2x80x9cHeteroarylxe2x80x9dxe2x80x94alone or in combination means a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group O, S, and N, and optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable aromatic ring is retained. Examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl, purinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzoturyl, indolyl, benzothiazolyl, benzoxazolyl, and the like. A substituted heteroaryl contains a substituent attached at an available carbon or nitrogen to produce a stable compound.
xe2x80x9cHeterocyclylxe2x80x9dxe2x80x94alone or in combination means a non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally benzo fused or fused heteroaryl of 5-6 ring members and/or are optionally substituted as in the case of cycloalkyl. Heterocycyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. The point of attachment is at a carbon or nitrogen atom. Examples of heterocyclyl groups are tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, dihydroindolyl, and the like. A substituted hetercyclyl contains a substituent nitrogen attached at an available carbon or nitrogen to produce a stable compound.
xe2x80x9cSubstituted heteroarylxe2x80x9d refers to a heterocycle optionally mono or poly substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
xe2x80x9cAralkylxe2x80x9d refers to the group xe2x80x94Rxe2x80x94Ar where Ar is an aryl group and R is lower alkyl or substituted lower alkyl group. Aryl groups can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
xe2x80x9cCycloalkylxe2x80x9d refers to a divalent cyclic or polycyclic alkyl group containing from 3 to 15 carbon atoms.
xe2x80x9cSubstituted cycloalkylxe2x80x9d refers to a cycloalkyl group comprising one or more substituents with, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
xe2x80x9cAlkyl cycloalkylxe2x80x9d denotes the group xe2x80x94R-cycloalkyl where cycloalkyl is a cycloalkyl group and R is a lower alkyl or substituted lower alkyl. Cycloalkyl groups can optionally be unsubstituted or substituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
xe2x80x9cOptionalxe2x80x9d and xe2x80x9coptionallyxe2x80x9d mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9coptional pharmaceutical excipientsxe2x80x9d indicates that a formulation so described may or may not include pharmaceutical excipients other than those specifically stated to be present, and that the formulation so described includes instances in which the optional excipients are present and instances in which they are not.
xe2x80x9cTreatingxe2x80x9d and xe2x80x9ctreatmentxe2x80x9d refer to any treatment of a disease in a mammal, particularly a human, and include:
(i) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it;
(ii) inhibiting the disease, i.e., arresting its development; or
(iii) relieving the disease, i.e., causing regression of the disease.
The compositions of this invention are useful for treating mammals in a therapy selected from the group consisting of protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal""s (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction. The treatment is accomplished using a therapeutically effective amount of at least one compound of this invention and/or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable excipient.
Compounds falling within the scope of this invention include the optical isomers (+) and (xe2x88x92) and Rxe2x80x94 and Sxe2x80x94 isomers of the above-identified compounds and mixtures thereof. This invention includes the individual isomers and all possible mixtures thereof.
All of the aforementioned embodiments include the pharmaceutically acceptable acid addition salts thereof, particularly the mono- and dihydrochlorides, and mixtures thereof.
The compounds having the general formula I can be prepared as outlined in Schemes 1-5. A general synthesis of the compounds of this invention is outlined in Scheme 1. Compound IV can be prepared by N-acylation of substituted anilines of general structure II with 2-substituted chloroacetylchloride III. Compound II is available commercially or readily prepared through reduction of the corresponding nitrobenzene derivative (acid/SnCl2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Some examples of commercially available substituted anilines of general structure II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline, 4-methylaniline, 2,4-dichloroaniline, 3,4-dichloroaniline, 2,5-dichloroaniline, 2,4-dichloroaniline, 2-chloroaniline, 3-chloroaniline, 2,6-difluoroaniline, 2,5-difluoroaniline, 3,4-difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline. 
Compound VI can be obtained by reacting compound IV with a N-protected substituted piperazine V through warming in an appropriate solvent (e.g. DMF, EtOH). Protection of the nitrogen of compound V is only required when it is useful to control the regiochemistry of the addition of Compound V with compound IV. In some cases, compound V can be obtained from commercial sources. Examples of commercially available compounds of general structure V include 2-methyl piperazine, 2,5-dimethyl piperazine and 2,6-dimethyl piperazine. Deprotection of compound VI can be accomplished using the standard conditions (e.g. for Boc group use TFA, for CBZ and benzyl use hydrogenation). Compound I can be prepared by reacting compound VII with epoxide VIII through warming in an appropriate solvent (ethanol, DMF). 
Epoxide VIII can be prepared as outlined in Scheme 2. Epoxidation of substituted allylbenzene XI using mCPBA or hydrogen peroxide can afford epoxide VIII (G. Majetich, R. Hicks, G. Sun and P. McGill, (1998), 63,2564-2573). Compound XIA (n=1) in turn can be prepared by reacting aldehyde IX with methylenetriphenylphosphorane under Wittig conditions or Horner Emmons conditions [Advanced Organic Chemistry, Eds. J. March, (1992), Wiley-Interscience publication and S. Pine, G. Shen and H. Hoang, Synthesis, (1991), 1]. The compound XIB (n=2) can also be conveniently prepared by coupling a halide with the general formula X with allyl magnesium bromide. In some cases compound XI can be obtained from commercial sources. Examples of commercially available compounds corresponding to the general structure XI include (where m=0) 3-fluorostyrene, 4-fluorostyrene, 2-chlorostyrene, 3-chlorostyrene, 4-chlorostyrene, 2,6-dichlorostyrene, 3,4-dichlorostyreneand 3,4-dimethoxystyrene. Other examples of commercially available compounds with the general structure XI include (where m=1) 4-methoxyallylbenzene, 2-hydroxyallylbenzene, 4,5-dimethoxyallylbenzene, 2-methylallylbenzene safrole and 1-allylnaphthalene. 
Compound V can be prepared as described in Scheme 3. Alkylation of compound XII with alkyl halides using t-BuLi as base can afford compound XIII as described by Pohlman et. al. (J. Org. Chem, (1997), 62, 1016-1022). Reduction of XIII using diborane can afford N-benzyl protected version of compound V after N-Boc deprotection with trifluoroacetic acid (TFA, for the diborane reduction see Jacobson et. al, J. Med. Chem, (1999), 42, 1123-1144). 
Compound V can also be prepared through standard coupling (eg. EDC or PyBroP) of D or L amino acids and standard deprotection (e.g., Boc removal by TFA treatment) as outlined in Scheme 4 [For preparations of diketopiperazines seexe2x80x94P. Cledera et al. Tetrahedron, (1998) p. 12349-12360 and R. A. Smith et al Bioorg. Med. Chem. Lett. (1998) p. 2369-2374]. Reduction of the diketopiperazine with diborane can afford the N-benzyl protected version of compound V.
Compound V also includes the bicyclic homologs of piperazine (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83, 3,8-diazabicyclo[3.2.1]octane 84, and 2,5-diazabicyclo[2.2.2]octane 85. 
Commercially available bicyclic analogs include (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83. Compounds 84, 85, and the (1R,4R) isomer of 83 can be prepared by published procedures (for 84 and 85xe2x80x94see Sturm, P. A. et al, J. Med. Chem. 1974, 17, 481-487; for 83 seexe2x80x94Barish, T. F. and Fox, D. E. J. Org. Chem., 1990, 55, 1684-1687).
A specific example of the preparation of a compound from this invention is disclosed in Scheme 5 to further illustrate how to prepare the compounds of this invention. In particular, 2,6-dichloroaniline was acylated with 2-chloroacetyl chloride 2 using saturated bicarbonate and ether (1:1) as base and co-solvent, respectively to afford the chloroacetamide derivative 3. Further reaction of compound 3 with piperazine afforded compound 5 through warming in ethanol. Reaction of compound 5 with epoxide 6 by warming both components in ethanol at reflux afforded piperazine derivative 7. 
Compound 8 is commercially available and was epoxidized using 3-chloroperoxybenzioc acid in dichloromethane as illustrated in Scheme 6. 
Four carbon epoxide 15 can be prepared by coupling commercially available 4-methoxybenzyl chloride with allylmagnesium bromide followed by oxidation with mCPBA as illustrated in scheme 7. 
The acid addition salts of the compounds of this invention may be converted to the corresponding free base by treating with a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of aqueous solvent, and at a temperature of between about 0 degrees C. and 100 degrees C. The free base form is isolated by conventional means, such as extraction with an organic solvent.
Salts of the compounds of this invention may be interchanged by taking advantage of differential solubilities and volatilities, or by treating with the appropriately loaded ion exchange resin. This conversion is carried out at a temperature between about 0xc2x0 C. and the boiling point of the solvent being used as the medium for the procedure. Administration of the active compounds and salts described herein can be via any of the accepted modes of administration for therapeutic agents. These methods include oral, parenteral, transdermal, subcutaneous and other systemic modes. The preferred method of administration is oral, except in those cases where the subject is unable to ingest, by himself, any medication. In those instances it may be necessary to administer the composition parentarally.
Depending on the intended mode, the compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage forms suitable for single administration of precise dosages. The compositions may include one or more conventional pharmaceutical excipients and at least one active compound of this invention or the pharmaceutically acceptable salts thereof and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.
The amount of active compound administered will, of course, be dependent on the subject being treated, the subject""s weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. However, an effective dosage is in the range of 0.1-30 mg/kg/day, preferably 0.5-20 mg/kg/day. For an average 70 kg human, this would amount to 7-2100 mg per day, or preferably 35-1400 mg/day. Since many of the effects of the compounds herein (protect skeletal muscles against damage resulting from trauma; protect skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication; treat shock conditions; preserve donor tissue and organs used in transplants; and treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal""s (variant) angina, stable angina, exercise induced angina, congestive heart disease, and myocardial infarction) are achieved through a similar mechanism (partial fatty acid oxidation inhibition) dosages (and forms of administration) are all generally within the same general and preferred ranges for all these utilities.
For solid compositions, conventional non-toxic solid include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used. The active compound as defined above may be formulated as suppositories using, for example, polyalkylene glycols, for example, propylene glycol, as the carrier. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975. The composition or formulation to be administered will, in any event, contain a quantity of the active compound(s), a therapeutically effective amount, i.e. in an amount effective to alleviate the symptoms of the subject being treated. For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. Such compositions may contain 10%-95% active ingredient, preferably 1-70%.
Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
A more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, e.g., U.S. Pat. No. 3,710,795, which is incorporated herein by reference. In another recent approach, the compositions of this invention can be administered orally in a sustained release dosage form using the compositions and/or methods disclosed in U.S. patent application Ser. No. 09/321,522, filed on May 27, 1999, the specification of which is incorporated herein by reference.
It is within the scope of this invention to administer one or more compounds of this invention to a mammal, and preferably to a human by other known routes of pharmaceutical dosage form administration including, but not limited to by bolus, intravenously, transdermally, through inhalation, sub-cutaneously, or any other therapeutic agent administration method or route know to one skilled in the art.
The following Examples are representative of the invention, but are not to be construed as limiting the scope of the claims.